Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C. D.; Rilling, H. C., in "Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981 and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway. The selective inhibition of this step should allow the essential pathways to isopentenyl tRNA, ubiquinone, and dolichol to proceed unimpeded. Squalene synthetase, along with HMG-CoA reductase has been shown to be down-regulated by receptor mediated LDL uptake (Faust, J. R.; Goldstein, J. L.; Brown, M. S. Proc. Nat. Acad. Sci. USA, 1979, 76, 5018-5022), lending credence to the proposal that inhibiting squalene synthetase will lead to an up-regulation of LDL receptor levels, as has been demonstrated for HMG-CoA reductase, and thus ultimately should be useful for the treatment and prevention of hypercholesterolemia and atherosclerosis.
The alkylations of allylic esters with other nucleophiles such as malonate esters, sulfonoacetate esters and methylenebissulfones, has been pioneered by Trost and others as follows:
1) Thompson, W.; Tucker, T.; Schwering, J.; Barnes, J., Tetrahedron Letters, 1990, 31, 6819-6822 PA1 2) Marshall, J.; Andrews, R.; Lebioda, L., J. Org. Chem., 1987, 52, 2378-2388 PA1 3) Trost, B., Angew. Chem. Int. Ed. Eng. 1989, 28, 1173-1192 PA1 4) Trost, B.; Verhoven, T., J. Am. Chem. Soc. 1979, 101, 1595-1597 PA1 R.sup.3 is alkyl, aryl, alkoxy or aryloxy; with a methylene bisphosphonate of the structure ##STR2## wherein R.sup.4 is alkyl in the presence of a palladium catalyst, preferably Pd[(C.sub.6 H.sub.5).sub.3 P].sub.4, and an inert organic solvent, preferably tetrahydrofuran, optionally in the presence of a ligand such as triphenylphosphine, to form the 3-alkenylidene-1,1-bisphosphonates of the structures ##STR3## wherein the alkene moiety in each of bisphosphonates III and IV is located .gamma., .delta. to the phosphonates.